Project Summary/Abstract The capacity of ?-cells to expand in response to insulin resistance is critical to develop type-2 diabetes and ?- cell proliferation is a major component for these adaptive responses. The long-term goal of our previous and proposed studies under this award is to understand the molecular mechanisms that regulate ?-cell mass and function. During the current funding period, we identified mTOR/raptor complex (mTORC1) as a major player in regulating ?-cell mass and insulin secretion. We uncovered the individual contribution of the mTORC1 downstream targets 4E-BP, S6 kinases (S6K) and ULK on the regulation of ?-cell growth, proliferation, survival, insulin processing and secretion. We also discovered a novel mTORC1/4E-BP2/eIF4E/SH2B1 positive feedback loop that increases IRS2 signaling. However, uncertainty remains as to how mTORC1 acting on 4E-BP2, S6K and ULK controls ?-cell mass and insulin secretion. The objective of this application is to build on these observations and determine how mTORC1 regulates ?-cell mass and insulin secretion. We hypothesize that mTORC1 regulates (i) ?-cell mass in a 4E-BP2/SH2B1 and JNK3-dependent manner and (ii) insulin secretion by regulating stages proximal to calcium influx and autophagy mediated process. The specific aims are (1) Establish how 4E-BP2/eIF4E acting on SH2B1 and JNK3 regulates ?-cell mass expansion. (2) Determine how mTORC1 modulates insulin secretion and adaptation to diabetogenic conditions. This proposal will provide important insights into the molecular mechanisms that govern ?-cell mass and insulin secretion by mTORC1. This information can be used to expand drug development opportunities for diabetes.